Sepsis is a systemic inflammatory response to infection. It is responsible for ~1 million hospital admissions and nearly half of all hospital deahs in the US alone. Considering it is the most expensive condition treated and because of concerns of increasing antibiotic-resistant microbes, sepsis has evolved into one of the most urgent medical issues. Because the cause of sepsis is heterogeneous and its clinical features are diverse, determining central regulators for effective host-directed therapies has been a considerable challenge. It is well established that sepsis promotes excessive cell dysfunction, including suppressed neutrophil and endothelial cell function. Neutrophils are a critical first lin of defense against bacterial spread and secondary infections, which is initiated by their attachment to endothelial cells lining blood vessels at the infectious locus. Neutrophils and endothelial cells express ADAM17, a membrane metalloprotease that regulates intravascular adhesion events in various manners. Our preliminary findings reveal that pronounced inflammation results in systemic activation of ADAM17, which in turn disrupts adhesion processes by neutrophils and endothelial cells critical for an effective host response. The objective of our study is to determine for the first time the in vivo role of ADAM17 in vascular dysfunction using a polymicrobial sepsis model, its activity in sepsis patients, and to assess the preclinical efficacy of selective ADAM17 inhibitors. Our hypothesis is that systemic activation of ADAM17 during the acute phase of sepsis promotes vascular dysfunction, shifting the balance of the early host response from bacterial clearance to inflammatory injury. The specific aims of our proposal are to establish the distinct in vivo contributions of ADAM17 in neutrophils and endothelial cells in promoting vascular dysfunction during sepsis using conditional knock-out mice (Aim 1); to determine the effects of ADAM17 inhibitors on neutrophil and endothelial cell intravascular adhesion and on early stage sequalae during sepsis (Aim 2); and to validate ADAM17's activity in sepsis patients and the therapeutic efficacy of its targeting after sepsis onset in preclinical studies (Aim 3). The impact of our study is that it investigates systemic ADAM17 activation as a pivotal mechanism of vascular dysfunction that disrupts neutrophil recruitment at sites of infection and enhances their detrimental activities in distal organs.